Atovaquone, 2-[trans-4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone (compound of formula (I))
is a useful medicine for the treatment and prophylaxis of Pneumocystis carinii infections. Atovaquone is potently active (in animals and in vitro) against Pneumocystis carinii, Plasmodia, and tachyzoite and cyst forms of Toxoplasma gondii. Due to its inhibitory effect in sensitive parasites, atovaquone can act by selectively affecting mitochondrial electron transport and parallel processes such as ATP and pyrimidine biosynthesis.
Atovaquone is approved for marketing in the US under the tradename Mepron® as tablets of 250 mg and an oral suspension which is indicated for the treatment and prophylaxis of Pneumocystis carinii infection. It is also available in combination with proguanil hydrochloride under the tradename Malarone® for the treatment and prevention of plasmodium falciparum malaria.
European Patent No. 123238 discloses 2-substituted-3-hydroxy-1,4-naphthoquinones, including atovaquone, which are said to be active against the human malaria parasite Plasmodium falciparum and also against Eimeria species such as E. tenella and E. acervulina, which are causative organisms of coccidiosis.
U.S. Pat. No. 5,053,432 and European Patent No. 123238 describe a process for preparing atovaquone (Scheme 1). The process as described in this patent proceeds by the reaction of 2-chloro-1,4-naphthoquinone and 4-(4-chlorophenyl)cyclohexane-1-carboxylic acid in the presence of silver nitrate and ammonium persulphate, followed by extraction with ether. This process gives an overall low yield due to the low yield produced in the key radical coupling stage.

A process for the preparation of atovaquone was also reported in Tetrahedron Letters, Vol. 39, 7629-7632 (1998), as shown in Scheme 2 below. This process prepares a mixture of cis and trans isomers of atovaquone by the reaction of an oxalate with 2-chloro-1,4-naphthquinone, in the presence of silver nitrate, ammonium persulphate and a phase transfer catalyst. The conversion to atovaquone was effected upon treatment with potassium hydroxide in methanol and recrystallisation from acetonitrile.

The disclosed process suffers from several drawbacks, as it requires purification by recrystallisation from acetonitrile. It also produces a low overall yield due to a low yield produced in the key radical coupling stage.
The object of this invention is therefore to develop an alternative process for the synthesis of atovaquone that does not suffer the draw backs of the prior art.
The processes herein described offer advantages over the prior art in that simpler reaction steps are included which increases the overall yield of the end product atovaquone. The processes herein described also use low cost starting materials. The processes herein described also do not include the use of silver nitrate (a heavy metal) which is expensive and may contaminate the final product with silver. Furthermore, the amount of silver in pharmaceuticals is tightly controlled by health authorities.
The process of the present invention avoids the use of highly undesirable agents such as acetonitrile, minimising environmental impact.
There is an unmet need for an improved process which provides higher yields of atovaquone, using reagents which are inexpensive while avoiding the use of undesirable reagents. The present invention provides such a process.